1. Seveso Disaster, and the Seveso and Seveso II Directives
Pertti J Hakkinen & 2005 Elsevier Inc. All rights reserved. The
Seveso Disaster The Seveso disaster began on July 10, 1976 at the
Industrie Chimiche Meda Societa` Azionaria (ICMESA) chemical plant
in Meda, Italy. This event became internationally known as the
Seveso disaster, after the name of the most severely affected
commu- nity. An increase in pressure due to an exothermic reaction
in a 2,4,5-trichlorophenol-production reac- tor caused the rupture
disk of the safety valve to burst. About 3000 kg of chemicals were
released into the air. The release included 2,4,5-trichlorophenol,
used in the manufacture of herbicides, and possibly up to 30 kg of
the dioxin TCDD (2,3,7,8-tetrachloro- dibenzo-p-dioxin). Dioxin rst
came to widespread public notice during the Vietnam War, when it
was identied as a component of the defoliant Agent Orange. Dioxin
has also been considered to be the most toxic human-made substance.
The chemicals released into the air from the chem- ical plant near
Milan in northern Italy were carried southeast by the wind towards
Lake Como. The dioxin cloud contaminated a densely populated area
about 6 km long and 1 km wide downwind from the site. The four most
impacted municipalities in- cluded Seveso (a 1976 population of 17
000), Meda (19 000), Desio (33 000), and Cesano Maderno (34 000).
Two other municipalities, Barlassina (6000) and Bovisio Masciago
(11 000), were subject to postaccident restrictions. Health
monitoring was extended to a further ve municipalities. The entire
affected area is part of the Brianza, one of the wealthiest and
most industrialized regions of Italy. The economy of this area at
the time of the disaster depended on small workshops and
industries, mainly engaged in manufacturing furniture. The Seveso
disaster had a traumatic effect on the minds of the local
populations because its seriousness was recognized only gradually.
People elsewhere in the world also experienced heightened concern
about chemical exposures and risks and the need for tighter
regulation of hazardous chemical manufacturing. The accident was
not immediately noticed since no one was at the plant when it
happened. One day later, ICMESA managers informed local authorities
of the escape of a cloud of herbicide that causes harm to
agriculture, stating that in all likeli- hood the aerosol mixture
which escaped consists of sodium trichlorphenate, caustic soda, and
solvent, but possibly other toxic substances as well. They
requested the authorities to warn the population, and samples were
sent by courier for examination to a company, Givaudan SA, in
Switzerland. Givaudan SA, once one of ICMESAs main customers, had
tak- en over ICMESA as a subsidiary in 1969. Two days after the
disaster, nearby residents were warned not to eat any vegetables
from their gardens. Four days after the disaster, the Technical
Director of Givaudan in Geneva informed the Technical Director of
ICMESA that the samples contained traces of TCDD. Authorities were
told much later about the TCDD. The Seveso disaster resulted in the
highest known TCDD exposure to residential populations, and has
possibly been the most systematically studied dioxin contamination
incident in history. The rst sign of human health problems was
burn- like skin lesions, appearing on children after the ac-
cident. Beginning in September of 1976, chloracne, a severe skin
disorder usually associated with dioxin, broke out on some people
who were most exposed. Authorities began an investigation ve days
after the accident, when large numbers of local animals such as
rabbits began to die. After a linkage to dioxin was made, over 700
hundred people living closest to the plant were evacuated within 3
weeks after the acci- dent. In all, up to 2000 people were treated
for dioxin poisoning. Approximately 4% of the local farm animals
died, and B80 000 additional animals were killed to prevent
contamination from ltering up the food chain. The Seveso disaster
areas were divided and sub- divided based on soil contamination
levels. Zone A, the most contaminated area with more than 50 mg of
TCDD per square meter and covering 110 ha, was completely evacuated
and fenced-off with entry pro- hibited. Zone A was later turned
into a park, the Seveso Oak Forest. In the next-most contaminated
areas, zone B (between 5 and 50 mg m 2 ) and zone R (below 5 mg m 2
), farming as well as consumption of local agricultural goods and
meats were strictly pro- hibited. Professor Paolo Mocarelli of the
University of Milano-Bicoccas Hospital of Desio was put in charge
of a laboratory setup two weeks after the accident to test people
for health problems. Dr. Mocarellis lab- oratory has conducted
neurological, obstetric, and other tests that have surpassed 1
million in number, and Dr. Mocarelli decided to save one sample of
blood from each person just in case it would be pos- sible to
measure very low levels of TCDD in small blood samples someday.
This became possible in 1987, and Dr. Mocarelli has worked with the
US Seveso Disaster, and the Seveso and Seveso II Directives 1
2. Centers for Disease Control and Prevention to anal- yze the
thousands of samples and to try to associate the levels with health
effects. Reconstruction of the disaster using the samples taken
over time has helped clarify how long dioxin stays in the human
body, and the different effects it has on children and adults. One
toxic effect of the Seveso dioxin exposure was on reproduction. In
the rst 7 years after the accident, a very high proportion of
females (46 females compared to only 28 males) were born to parents
who were exposed to the chemical cloud. This was the rst time a
chemical had been obser- ved to change the sex ratio, implicating
dioxin as a hormone disrupter. TCDD is associated with in- creased
fetal loss and reduced birth weight in animal studies. The Seveso
Womens Health Study (SWHS) is a retrospective cohort study of
people who resided in the most contaminated areas, zones A and B.
Serum samples collected near the time of the explosion were
analyzed for TCDD. Also analyzed were pooled serum samples
collected in 1976 from females who resided in the unexposed zone to
assess concurrent background exposures to other dioxins, furans,
and polychlorinated biphenyls (PCBs). The youngest chil- dren had
the highest TCDD levels, which decreased with age at explosion
until B13 years of age and were essentially constant thereafter.
The zone of res- idence and age were the strongest predictors of
TCDD level. Chloracne, nearby animal mortality, location (outdoors
versus indoors) at the time of ex- plosion, and consumption of
homegrown food were also related to serum TCDD levels. The serum
pools from the unexposed zone residents had TCDD con- centrations
and average total toxic equivalent (TEQ) concentrations that
suggested that the background exposure to dioxins, furans, and PCBs
unrelated to the explosion may have been substantial. Therefore,
the early SWHS studies that considered only TCDD exposure may have
underestimated health effects due to total TEQ concentrations. The
early part of the SWHS looked at the relation of pregnancy outcome
to maternal TCDD levels measured in serum collected shortly after
the explo- sion. Ninety-seven pregnancies (10.9%) ended as
spontaneous abortions. TCDD was associated with a nonsignicant
adjusted decrease in gestational age and a 2050% nonsignicant
increase in the odds of preterm delivery. The exposed population
also re- ported symptoms of immune system and ne- urological
disorders; however, studies found no link to dioxin. Increases in
some forms of cancer found in the exposed population have suggested
a link be- tween dioxin and some cancers. Further research on the
children of victims of the disaster is being conducted, as is
research focusing on dioxins long-term carcinogenic properties. For
ex- ample, 25 years after the Seveso disaster, human milk from
mothers in Seveso was found to have TCDD concentrations more than
twice as high as those in central Milan and elsewhere in the areas
near Seveso. This suggests that breastfed infants in Seveso might
have appreciable amounts of TCDD in their body fat; however, the
health consequences remain to be determined. In addition to
monitoring victims and offspring of the accident, another type of
monitoring that con- tinues concerns the Seveso Oak Forests two
large concrete tanks lying beneath the surface. These tanks are the
resting place of the top 40 cm of soil removed after the disaster,
and also are the nal resting place of the contaminated animals that
were slaughtered, and the factory (disassembled brick by brick by
workers in protective suits) and other buildings exposed to the
cloud. The area around the tanks is monitored for leaks, and the
soil is said to now have lower dioxin levels than in average areas.
The area is now a place where families can gather and animals have
returned to the park and adjacent nature reserve. After the Seveso
disaster, investigation of the po- tential emission sources in the
area and studies of people not exposed to the cloud indicated that
com- bustion of wood residues from furniture factories might be an
additional and perhaps substantial local source of dioxins, furans,
and PCBs. The Seveso Directive In 1982, the European Unions Council
Directive 82/501/EEC on the major-accident hazards of cer- tain
industrial activities, also known as the Seveso Directive, was
adopted. The Directive was mostly designed to promote information
ow and created the requirement that each Member State (i.e., each
country belonging to the European Union) appoint a Competent
Authority to oversee safety issues. The Seveso Directive was
amended twice, following major accidents at the Union Carbide
chemical fac- tory in Bhopal, India in 1984 (a leak of methyl
isocyanate caused thousands of deaths), and at the Sandoz chemical
warehouse in Basel, Switzerland in 1986 (re-ghting water
contaminated with mercury, organophosphate pesticides and other
chemicals caused massive pollution of the Rhine River and the death
of hundreds of thousands of sh). Both amendments, broadened the
scope of the Directive, in particular to include the storage of
dangerous substances. 2 Seveso Disaster, and the Seveso and Seveso
II Directives
3. The Seveso Directive covered all European Union Member
States, and held them responsible for ens- uring that the relevant
national institutions do what is required for adequate risk
management. The entire Directive was also driven by a concern for
prevent- ion, including those parts that relate to post-accident
activities. For example, terms such as industrial activity,
manufacturer, major accident, and danger- ous substances were
dened, the types of produc- tion, operations, and storage
activities that are subject to regulation were described, and the
dangers that are anticipated were noted. Member States were
required to ensure that man- ufacturers identify existing major
accident hazards, and that they adopted all appropriate safety
meas- ures, including information, training, and equipment for
workers. Further, Member States must set up Competent Authorities
that will take responsibility for receiving such a notication,
examining the information provided, organizing inspections or other
measures of control, and ensuring that off-site emergency plans are
prepared. The manufacturers were also required to provide the
Competent Authorities with a notication containing detailed and
updated information on safety precautions and other matters. In
addition, Member States were held responsible for assuring that
persons liable to be affected by a major accident were informed in
an appropriate manner of the safety measures and of the correct
behaviour to adopt in the event of an accident. Article 8 of the
Seveso Directive was noteworthy in its content because the safety
of people outside hazardous installations was taken into account
for the rst time in Europe (before this, only workers might have
had the right to be informed). Informa- tion that had previously
been for experts alone was opened-up to inspection by, and input
from, the public. Another article of the Directive required Member
States to take the necessary measures to ensure that the
manufacturer immediately provided full and detailed information
about an accident to the competent authorities; they must in turn
were to ensure that all necessary measures were taken and that full
analysis of the accident was accomplished whenever possible. The
European Commission was put in charge of setting up a register
containing a summary of major accidents that occur within the
European Union, including an analysis of causes, ex- perience
gained, and measures taken to enable Mem- ber States to use this
information for prevention purposes. The Seveso Directive also led
the way to similar initiatives on other issues, for example, in
environ- mental management and public health. This included the
mandating of measures to encourage improvem- ents in occupational
safety and health; minimum safety and health requirements for the
workplace, measures related to biotechnology; the freedom of access
to environmental information; and public information about
radioactive emergencies. Beyond Europe, the Seveso Directive was
important for many international organizations, for example, the
World Bank, the United Nations Environment Programme, the Council
of Europe, the International Atomic Energy Agency, the Ofce of the
United Nations Dis- aster Relief Coordinator (UNDRO), the World
Health Organization, and the International Labour Organization
(ILO). Further, the Organization for Economic Cooperation and
Development (OECD) has focused much attention to accident
prevention and response and has published a number of recom-
mendations, some of which are specifically addressed to public
information and public participation in de- cision-making. The
Seveso II Directive In 1996, Council Directive 96/82/EC on the
control of major-accident hazards, also known as the Seveso II
Directive, was adopted. The Seveso II Directive replaced the
original Seveso Directive, and Member States had up to 2 years to
bring into force the national laws, regulations and administrative
provi- sions to comply. Important changes and new con- cepts
included a revision and extension of the scope of the Seveso
Directive, the introduction of new requirements relating to safety
management systems, emergency planning and land-use planning, and a
reinforcement of the provisions on inspections to be carried out by
Member States. Further, Member States can maintain or adopt
stricter measures than those contained in the Seveso II Directive.
The Seveso II Directive covers industrial activities and the
storage of dangerous chemicals, with larger quantities of a
chemcial leading to more control measures. A company holding a
quantity of danger- ous chemical less than Seveso IIs lower
threshold levels is not covered by this legislation, but will be
proportionately controlled by general provisions on health, safety
and the environment provided by other legislation not specific to
major-accident hazards. Important areas excluded from the scope of
the Seveso II Directive include nuclear safety, the trans- port of
dangerous substances and intermediate tem- porary storage outside
establishments and the transport of dangerous substances by
pipelines. All operators of establishments coming under the scope
of the Seveso II Directive need to send a notication to the
competent authority, and need to Seveso Disaster, and the Seveso
and Seveso II Directives 3
4. establish a Major-Accident Prevention Policy. In ad- dition,
operators of upper tier establishments (i.e., holders of high
levels of a dangerous chemical) need to establish a Safety Report,
a Safety Management System, and an Emergency Plan. Member States
have the obligation to report major accidents to the Commission. In
order to fulll its information obligations toward the Member
States, the European Commission has created the Major Accident
Reporting System (MARS) database to store and retrieve accident
information reported by the Member States, and a Community
Documenta- tion Centre on Industrial Risks (CDCIR) was estab-
lished to collect, classify, and review materials relevant to
industrial risks and safety. In order to assist Member States with
the inter- pretation of certain provisions of the Seveso II Di-
rective, the European Commission in co-operation with the Member
States developed documents on the preparation of a safety report,
guidelines on a major accident prevention policy and safety
management system, explanations and guidelines on harmonized
criteria for dispensations, guidance on land-use planning, guidance
for the content of information to the public, and guidance on
inspections. In addi- tion, a series of answers to frequently asked
ques- tions has been published and regularly updated. These
guidance documents and the answers to fre- quently asked questions
have no legal status, but do provide valuable guidance to
industrial operators as well as enforcement authorities within the
European Union. See also: Bhopal; Dioxins; European Union and Its
Eu- ropean Commission; International Labour Organization (ILO);
Organisation for Economic Cooperation and Development. Further
Reading Bertazzi PA, Bernucci I, Brambilla G, Consonni D, and
Pesatori AC (1998) The seveso studies on early and long- term
effects of dioxin exposure: A review. Environmental Health
Perspectives 106(Suppl. 2): 625633. Eskenazi B, Mocarelli P, Warner
M, et al. (2003) Maternal serum dioxin levels and birth outcomes in
women of Seveso, Italy. Environmental Health Perspectives 111:
947953. Eskenazi B, Mocarelli P, Warner M, et al. (2004) Rela-
tionship of serum TCDD concentrations and age at exposure of female
residents of Seveso, Italy. Environ- mental Health Perspectives
112: 2227. Fattore E, Di Guardo A, Mariani G, et al. (2003) Poly-
chlorinated dibenzo-p-dioxins and dibenzofurans in the air of
Seveso, Italy, 26 years after the explosion. Environ- mental
Science and Technology 37: 15031508. Landi MT, Bertazzi PA,
Baccarelli A, et al. (2003) TCDD- mediated alterations in the
AhR-dependent pathway in Seveso, Italy, 26 years after the
accident. Carcinogenesis 24: 673680. Pesatori AC, Consonni D,
Bachetti S, et al. (2003) Short- and long-term morbidity and
mortality in the population exposed to dioxin after the Seveso
accident.. Industrial Health 41: 127138. Weiss J, Papke O, Bignert
A, et al. (2003) Concentrations of dioxins and other
organochlorines (PCBs, DDTs, HCHs) in human milk from Seveso, Milan
and a Lombardian ru- ral area in Italy: A study performed 25 years
after the heavy dioxin exposure in Seveso. Acta Paediatrica 92:
467472. Relevant Website http://www.europa.eu.int European
Commission, Chem- ical Accident Prevention, Preparedness and
Response. Shampoo Paul Sterchele Published by Elsevier Inc. * TRADE
NAMES: Neutrogena; Head and Shoulders; Prell; Pert; Johnsons;
Pantene * CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Combi- nation of
nonionic, amphoteric, and anionic surfactants Uses Shampoos are
rinse-off products used to cleanse the hair and scalp; they are
available in noncoloring and coloring formulations. Lindane
shampoos are avail- able for the treatment of lice; antidandruff
formula- tions are also available to control the symptoms of
dandruff and seborrheic dermatitis. Exposure Routes and Pathways
Ingestion is a common route of exposure. Ocular and dermal
exposures occur as well. Toxicokinetics There is minimal absorption
of anionic, nonionic, and amphoteric surfactants. Antidandruff
shampoos may contain zinc pyridinethione and selenium 4
Shampoo
5. sulde. The pharmacokinetics of zinc pyridinethione have been
evaluated via multiple routes (percutane- ous, oral, intravenous,
intraperitoneal) and in several species (rats, rabbits, monkeys,
dogs).. Selenium sulde is poorly absorbed. Peak serum levels of
lin- dane (an ingredient in shampoos used to treat lice
infestation) occur B6 h after a single dermal appli- cation.
Lindane is highly lipid soluble and is stored in adipose tissue.
Lindane is metabolized in the liver to chlorophenols. Amphoteric,
anionic, and nonionic surfactants are eliminated in the urine and
feces. Selenium salts are excreted in the urine. Lindane has a
half-life of B18 21 h following dermal application. Mechanism of
Toxicity The surfactants and other adjuvants in shampoo are
primarily irritants, and most dermal, ocular, or gas- trointestinal
toxicity is a consequence of the irritant properties. Acute and
Short-Term Toxicity (or Exposure) Animal In general, nonlindane
shampoos do not produce toxicity. Transient irritant effects are
expected, espe- cially in the event of ocular exposure. Exposure to
lindane shampoos can produce vomiting, tremors, increased
salivation, and seizures. Treatment is aimed at appropriate
gastrointestinal decontamina- tion and control of seizures. Human
Nonionic and anionic surfactants and selenium and zinc pyrithione
shampoos are irritants by nature. Nausea and vomiting can occur
following ingestion in large volumes. Spontaneous emesis is common.
Persistent vomiting has the potential to cause uid and electrolyte
imbalance. In general, gastrointesti- nal irritation is
self-limiting. Acute ingestion of lindane shampoo does have the
potential to cause central nervous system excitation. Toxicity can
occur when children ingest one tea- spoon or more of 1% lindane
shampoo. Ingestion of one tablespoon or more of lindane shampoo may
result in signicant toxicity. Symptoms of lindane toxicity include
agitation, tremors, seizures, and res- piratory depression. Chronic
Toxicity (or Exposure) Human Chronic dermal application of 1%
lindane shampoo does have the potential to cause lindane toxicity,
so it is not uncommon for products to contain precau- tionary
labeling to avoid the reapplication of lindane products within at
least a few months after use. Clinical Management Dilution is
generally all that is required in exposures to
nonlindane-containing shampoos. If spontaneous emesis does not
occur, then it is unlikely that a large ingestion occurred, and
mild to moderate, transient gastrointestinal distress is likely to
be the only sequelae. If persistent vomiting occurs, then uid and
electrolytes should be monitored. In toxic exposures to lindane
shampoos, basic and advanced life-support measures should be
utilized as needed. Emesis is not recommended in oral expo- sures
to lindane. Gastric lavage utilizing saline cathartics is
recommended; milk and fatty foods should not be administered in
oral lindane exposures since this may enhance absorption. See also:
Lindane; Surfactants, Anionic and Nonionic. Relevant Websites
http://www.ctfa.org US Cosmetic, Toiletry, and Fragrance
Association (CTFA). http://hpd.nlm.nih.gov US National Library of
Medicine, Household Product Database and ToxTown. The Household
Products Database links several thousand US consumer brands to
health effects from Material Safety Data Sheets (MSDSs) provided by
the manufac- turers, and allows scientists and consumers to
research products based on chemical ingredients. Shampoo 5
6. Shellsh Poisoning, Paralytic F Lee Cantrell & 2005
Elsevier Inc. All rights reserved. This article is a revision of
the previous print edition article by Gaylord P Lopez, volume 3, p.
137, & 1998, Elsevier Inc. Background Information Paralytic
shellsh poisoning is a constellation of clinical effects caused by
ingestion of contami- nated shellsh found on the East and West
coasts of the United States and Canada, the coasts around Japan,
and coastal areas from southern Norway to Spain. Implicated sources
(shellsh) are mussels, clams, scallops, univalve mollusks, starsh,
xanthid crabs, sand crabs, and turban shells. Exposure Routes and
Pathways Ingestion of toxin-infected bivalve shellsh is the route
of exposure. There is no reliable taste, smell, or color to detect
contaminated shellsh. The toxin is not destroyed or inactivated by
heating or cooking. Toxicokinetics The toxin is water soluble and
absorbed through the oral mucosa and small intestine. Mechanism of
Toxicity Neosaxitoxin, saxitoxin, and gongantoxin IIV block
transmission of impulses between nerve and muscle. They also block
sodium channels in nerve and skeletal muscle, inhibiting the nerve
and muscle action potential, thereby blocking nerve conduction and
muscle contraction. Acute and Short-Term Toxicity (or Exposure)
Animal Shags, terns, and cormorants may develop inam- mation of the
gastrointestinal tract, hemorrhages in the base of the brain, and
other hemorrhages. Human Common initial effects include numbness in
the lips, tongue, and ngertips within a few minutes of inges- tion.
This numbness may spread to the extremities and then to the
remainder of the body causing weakness and even muscle paralysis.
Gastrointestinal symptoms are less common and consist of nausea and
vomiting. Other symptoms include nystagmus, temporary blind- ness,
irregular heartbeats, drops in blood pressure, headache, dizziness,
difculty in swallowing, and loss of gag reex. Symptoms may persist
for weeks. Clinical Management Basic and advanced life-support
measures should be utilized as necessary. Treatment is entirely
symp- tomatic and supportive. Gastrointestinal deconta- mination
with activated charcoal may be used depending upon the patients
clinical status, the his- tory of the ingestion, and the time since
the ingestion. Mechanical ventilation may be required for patients
with decreased respiratory function. See also: Red Tide; Saxitoxin.
Further Reading Gessner BD and Middaugh JP (1995) Paralytic shellsh
poisoning in Alaska: A 20-year retrospective analysis. American
Journal of Epidemiology 141: 766770. Morbidity and Mortality Weekly
Report (1991) Paralytic shellsh poisoning Massachusetts and Alaska,
1990. MMWR 40: 157161. 6 Shellsh Poisoning, Paralytic
7. Shigella Melanie J Karst & 2005 Elsevier Inc. All rights
reserved. This article is a revision of the previous print edition
article by Vittoria Werth, volume 3, p. 138, & 1998, Elsevier
Inc. Name of the Organism Shigella spp. (Shigella sonnei, S.
boydii, S. exneri, and S. dysenteriae). Description Shigella are
Gram-negative, nonmotile, nonsporefor- ming, facultatively
anaerobic, rod-shaped bacteria. Shigella are differentiated from
the closely related Escherichia coli on the basis of pathogenicity,
physiology (failure to ferment lactose or decarboxy- late lysine),
and serology. The genus is divided into four serogroups with
multiple serotypes: A (S. dysenteriae, 12 serotypes); B (S. exneri,
6 sero- types); C (S. boydii, 18 serotypes); and D (S. sonnei, 1
serotype). Sources of Exposure/Transmission Shigellosis, also known
as bacillary dysentery, is caused by several bacteria of the genus
Shigella. Contamination of foods is through the fecal-oral route.
Fecally contaminated water and unsanitary handling of food are the
most common causes of contamination. Foods that are frequently
associated with shigellosis include salads (potato, tuna, shrimp,
macaroni, and chicken), raw vegetables, milk and dairy products,
and poultry. Any foods that require considerable handling during
preparation are often involved in shigellosis. Epidemiology
Shigellosis accounts for less than 10% of foodborne illness in the
United States. Bacillary dysentery con- stitutes a signicant
proportion of acute intestinal disease in the children of
developing countries. Shigellosis is endemic in developing
countries where sanitation is poor. Typically 1020% of enteric dis-
ease, and 50% of the bloody diarrhea or dysentery of young
children, can be characterized as shigellosis. In developed
countries, single-source, food, or water- borne outbreaks occur
sporadically, while cases of endemic shigellosis can be found in
some areas with substandard sanitary facilities. Dose An infective
dose may be as few as 10 cells depending on the age and condition
of the host. The time of onset of symptoms is somewhat inuenced by
the size of the challenge. Mechanism of Toxicity The disease is
caused when virulent Shigella organ- isms attach to, and penetrate,
epithelial cells in the intestinal mucosa. The cells then multiply
intracellularly and spread to neighboring epithelial cells
resulting in tissue destruction. Some strains pro- duce enterotoxin
and Shiga toxin. The hallmarks of shigellosis are bacterial
invasion of the colonic epi- thelium and inammatory colitis. These
conditions are interdependent processes amplied by local release of
cytokines and by the inltration of inammatory elements. Virulence
involves both chromosomal- and plasmid-coded genes: including (1)
siderophores that are iron-chelating compounds; (2) cytotoxins that
cause cell necrosis; (3) Shiga toxins, a family of potent
cytotoxins that inhibit protein synthesis and may play a role in
progression of mucosal lesions; and (4) chro- mosomal genes that
control lipopolysaccharide an- tigens in cell walls which may
enhance cytotoxicity of Shiga toxins on endothelial cells. Host
Defenses Inammation, copious mucus secretion, and regene- ration of
the damaged colonic epithelium limit the spread of colitis and
promote spontaneous recovery. Serotype-specific immunity is induced
by a primary infection, suggesting a protective role as antibodies
recognize the lipopolysaccharide somatic antigen. Other Shigella
antigens include enterotoxins, cyto- toxin, and plasmid-encoded
proteins that induce bac- terial invasion of the epithelium. The
protective role of immune responses against these antigens is
unclear. Diagnosis of Human Infection/Illness Colitis in the
rectosigmoid mucosa, with concomi- tant malabsorption, results in
the characteristic sign of bacillary dysentery: diarrhea tinged
with blood and mucus. Shigellosis can be correctly diagnosed in
most patients on the basis of fresh blood in the stool; however,
watery, mucoid diarrhea may be the only symptom of many Shigella
infections. This disease differs from profuse watery diarrhea, as
is commonly seen in choleraic diarrhea or in enterotoxigenic
Shigella 7
8. E. coli diarrhea, in that the dysenteric stool is scant and
contains blood, mucus, and inammatory cells. Any clinical diagnosis
should be conrmed by se- rological identication of a culture
isolated from stool. It is difcult to detect organisms in foods
with current methods. Nature of the Disease The onset of symptoms
of shigellosis is usually 1250 h. The most common symptoms are
abdom- inal pain, cramps, vomiting, and blood or mucus in stools.
Infections may be associated with mucosal ulceration, rectal
bleeding, and drastic dehydration. Death from Shigellosis may be as
high as 1015% with some strains. Sensitive populations such as the
elderly, infants, and immunocompromised individu- als are more
susceptible to complications from the disease. The average duration
of symptoms in untreated adults is 7 days, and the organism may be
cultivated from stools for 30 days or longer. Other complications
may include; lethargy, delir- ium, seizure, encephalopathy,
hemolytic-uremic syn- drome, septicemia, Reiter syndrome,
hepatitis, rectal prolapse, myocarditis, and toxic mega colon.
Clinical Management Prevention of fecaloral transmission is the
most effective control strategy. Severe dysentery is treated with
ampicillin, trimethoprim-sulfamethoxazole, or a 4-uorquinolone such
as ciprooxacin. Vaccines are not currently available. Dehydration
is the most common complication of shigellosis. Supportive care
with uids and electrolyte replace- ment may be required. See also:
Food and Drug Administration, US; Food Safety and Toxicology;
Gastrointestinal System. Relevant Websites http://vm.cfsan.fda.gov
US Food and Drug Administra- tion. Center for Food Safety &
Applied Nutrition. Foodborne Pathogenic. Microorganisms. and
Natural Toxins Handbook. Shigella spp. http://www.who.int World
Health Organization. In- itiative for Vaccine Research (IVR).
Shigella. http://www.amm.co.uk Association of Medical Micro-
biologists. The Facts about Shigella Infection and Bacillary
Dysentery. What is dysentery? Short-Term Exposure Limit See
Occupational Exposure Limits. Sick Building Syndrome Michael
Hodgson Published by Elsevier Inc. Sick building syndrome (SBS) is
a term used to de- scribe ofce worker discomfort and medical symp-
toms related to buildings and pollutant exposures, work
organization, and personal risk factors. A wide range of
definitions exists. Symptoms commonly considered integral parts of
the syndrome are listed in Table 1. In recent years, with increased
unders- tanding, odors have generally been dropped from the list
and chest symptoms have been included under mucous membrane
irritation. The problem may be viewed from the perspectives of (1)
medicine and health sciences, to dene symp- toms related to work
indoors and their associated pathophysiologic mechanisms; (2)
engineering, based on design, commissioning, operations, and
mainte- nance strategies and difculties; and (3) exposure
assessment, the formal measurement of specific pol- lutants. Health
and People Since the mid-1970s, increasingly voiced ofce worker
discomfort has been studied in formal ways Table 1 Sick building
syndrome Mucous membrane irritation Eye, nose, and throat itching
and irritation Central nervous system symptoms Headaches, fatigue,
difculty concentrating, lethargy Chest tightness and asthma- like
symptoms (without true wheezing) Skin itching and irritation Odors
Diarrhea 8 Sick Building Syndrome
9. including eld epidemiologic studies using buildings or
workstations as the sampling unit to identify risk factors and
causes, population-based surveys to dene prevalence, chamber
studies of humans to dene effects and mechanisms, and eld
intervention studies. Cross-Sectional and CaseControl Studies
Approximately 30 cross-sectional surveys have been published and
were reviewed by Mendell in 1993. Many of these have included
primarily nonproblem buildings, selected at random. These
consistently demonstrate an association between mechanical
ventilation and increasing levels of symptoms. Addi- tional risk
factors have been dened in several case control studies. Table 2
presents a grouping of widely recognized factors. Many of these
factors overlap. For some, path- ophysiologic explanations exist.
Women are con- sidered more likely to voice discomfort at any given
level of exposure and are exposed, on average, to higher levels of
pollutants, such as volatile organic compounds (VOCs) and
particulates, associated with symptoms. Factor and principal
components analyses of ques- tionnaire responses in cross-sectional
surveys have explored the interrelationship of various symptoms.
Consistently, symptoms related to a single organ sys- tem have
clustered together more strongly than symptoms relating different
organ systems. That is, eye irritation, eye tearing, eye dryness,
and eye itching all appear to correlate very strongly, and little
benet is obtained from looking at multiple symptoms. Data suggest
that irritation among ofce workers does not represent a single
distribution, but that sus- ceptible subpopulations exist.
Experimental studies, in chambers, show that atopic individuals
usually have much lower irritation thresholds for agents commonly
found indoors, even when their atopy is not active. In addition,
the presence of tear-lm in- stability, from Sicca complex, aging,
or other under- lying causes, poses an increased risk for
irritation. Controlled Exposure Studies Animal testing to determine
irritant properties and thresholds has become standard. A consensus
meth- od, American Society for Testing and Materials E, is widely
regarded as the basis. This method has been used to develop
structureactivity relationships, to demonstrate that more than one
irritant receptor may exist in the trigeminal nerve, and to explore
the interaction of multiple exposures. Recently, it has been used
to demonstrate the irritating properties of ofce equipment
offgassing. In keeping with this method, several approaches have
been developed to document methods and doseresponse relationships
for irritation in humans. This work suggests that, at least for
nonreactive compounds such esters, aldehydes, ketones, alcohols,
carboxylic acids, aromatic hydrocarbons, and pyri- dine, the
percentage of vapor pressure saturation of a compound is a
reasonable predictor of its irritant potency. Specific physical
properties of molecules predict overall irritation potential. This
work is based on the identication of irritant thresholds for
homologous series of specific agents. Quantitative
structureactivity relationships derived from such work suggests a
reasonable model to explain muco- sal irritation. Controlled
exposure studies of volunteers in stain- less steel chambers have
been performed. Most have involved exposure to one specific mixture
of VOCs; for example, the work of Molhave and Nielsen in 1992.
These studies consistently document relation- ships between
symptoms and increasing exposure levels. Ofce workers who perceived
themselves as susceptible to the effects of usual levels of VOCs
indoors demonstrated some impairment on standard tests of
neuropsychological performance. Healthy volunteers, on the other
hand, demonstrated mucous membrane irritation and headaches at
exposures in the range of 1025 mg m 3 but no changes on ne-
uropsychological performance. Recently, ofce workers demonstrated
similar symptoms after simu- lated work in environments where
pollutants were Table 2 Risk factors for and causes of the sick
building syn- drome Personal Atopy (allergies, asthma, eczema)
seborrheic dermatitis Work stress Gender Lower job status and pay
Increased tear-lm break-up time Work activities More time spent at
photoduplication Carbonless copy paper More time at video display
terminals Increasing amounts of time spent at workstation Building
factors Mechanical ventilation Inadequate maintenance High-eecing
surfaces (high surface area surfaces such as carpets and drapes)
Carpets Recent renovation Inadequate operations strategies Sick
Building Syndrome 9
10. generated from commonly used ofce equipment. Animals, using
a standardized test of irritant potency, reacted similarly.
Population-Based Studies At least three population-based studies
have been published in Sweden, Germany, and the United States. The
questionnaires differed considerably, and the studies do not allow
prevalence estimate comparisons. Nevertheless, between 20% and 35%
of respondents were thought to have complaints. Mechanisms A number
of potential mechanisms and objective measures to explain and
examine symptoms within specific organ systems have been identied.
None of these have a high predictive value for the presence of
disease and are not suitable for clinical diagnostic use. They are
useful in eld and laboratory investigations. These mechanisms and
measures were reviewed by Doty and co-workers in 2004. Both
allergic and irritant mechanisms have been proposed as explanations
for eye symptoms. More rapid tear-lm break-up time, a measure of
tear lm instability, is associated with increased levels of
symptoms. Fat-foam thickness measurement and photography for
documentation of ocular erythema have also been used. Some authors
attribute eye symptoms at least in part to increased individual
susceptibility based on those factors. In addition, of- ce workers
with ocular symptoms have been dem- onstrated to blink less
frequently when working at video display terminals. Conjunctival
staining with uorescent dyes is a common clinical test for con-
junctivitis sicca. Nose Both allergic and irritant mechanisms have
been proposed as explanations for nasal symptoms. Meas- ures that
have successfully been used include nasal swabs (eosinophils),
nasal lavage or biopsy, acoustic rhinometry (nasal volume),
anterior and posterior rhinomanometry (plethysmography), and
measures of nasal hyperreactivity (visual, using a dental pros-
thesis as a head xative, and using an ear surgery microscope to
measure distances and swelling). Central Nervous System
Neuropsychological tests have been used to docu- ment decreased
performance on standardized tests both as a function of controlled
exposure and as a function of symptom presence. Engineering and
Sources Beginning in the late 1970s, the National Institute for
Occupational Safety and Health responded to re- quests for help in
identifying causes of occupant dis- comfort in buildings. Although
no standard investigative protocol was used, the primary cause of
problems was attributed to ventilation systems B50%),
microbiological contamination (35%), strong indoor pollution
sources (tobacco, 3%; oth- ers, 14%), pollutants entrained from the
outside (15%), and the remainder unknown. On the other hand, Woods
and Robertson published two well- known series of engineering
analyses of problem buildings, documenting on average three
problems that could be the source (Table 3). The current
professional ventilation standard (ASHRAE 62-89) suggests two
approaches to vent- ilation: a ventilation rate procedure and an
air quality procedure. The former provides a tabular approach to
ventilation requirements: ofce buildings require 20 ft3 of outside
air per occupant per minute to maintain occupant complaint rates of
environmental discomfort at below 20%. This assumes relatively weak
pollution sources. When stronger sources are present, the same rate
will provide less satisfaction. For example, when smoking is
permitted at usual rates (according to data from the early 1980s),
B30% of occupants will complain of environmental discomfort. The
second approach requires the selec- tion of a target concentration
in air (e.g., particulates, VOCs, and formaldehyde), information on
emission rates (pollutant per time per mass or surface), and Table
3 Dened engineering problems in series of problem buildings Problem
category Physical cause Frequency Woods Robertson System design
Inadequate outdoor air 75 64 Inadequate distribution 75 46
Equipment Inadequate ltration 65 57 Inadequate drain lines and pans
60 63 Contaminated ducts and liners 45 38 Humidier malfunction 20
16 Operations Inappropriate control strategies 90 Inadequate
maintenance 75 Thermal and contaminant load charges 60 10 Sick
Building Syndrome
11. derives the ventilation requirements. Although this is an
intellectually much more satisfying procedure, it remains elusive
because of inadequate emissions data and disagreement on target
concentrations. In the past, odors were included under the et-
iologic list of SBS. A recent publication by Boswell and co-workers
provide at least an overview of com- mon odor sources. The single
largest source was plumbing, such as dried-up traps (16%), followed
by maintenance supplies (14%), renovations (11%), and ventilation
(8%). Pollutants Environmental scientists have generally dened ex-
posure and health effects on a pollutant-by-pollutant basis. In
indoor environments these include multiple air pollutants (i.e.,
2050 different VOCs, including formaldehyde and other aldehydes),
microbial prod- ucts (including spores, cell fragments, viable
organ- isms, and secretion products), and reactive agents such as
ozone, bers, and others. The American Thoracic Society dened six
important categories listed in Table 4. Environmental criteria have
been established for many of these, but the utility and
applicability of such criteria for indoor environments is
controversial for at least four reasons. For example, the goals of
the threshold limit values often do not include preventing
irritation, a primary concern in indoor environments with
requirements for close eye work at video display terminals. For
most of the pollutant categories, the problem of interactions,
commonly termed the mul- tiple contaminants problem, remains
inadequately dened. Even for agents that are thought to affect the
same receptor, such as aldehydes, alcohols, and ketones, no
prediction models are well established. Finally, the definition of
representative compounds for measurement is unclear. That is,
pollutants must be measurable, but complex mixtures vary in their
composition. It is unclear whether the chronic residual odor
annoyance from environmental tobacco smoke correlates better with
nicotine, particulates, carbon monoxide, or other pollutants. The
measure total volatile organic compounds is meanwhile considered an
interesting concept but is not consider- ed for practical purposes
because the various components have such radically different
effects. Par- ticulates found indoors may differ in composition
from those found outdoors because lter sizes affect entrained
concentrations and indoor sources may differ from outdoor sources.
Finally, emerging data suggest that reactive indoor pollutants may
interact with other pollutants and lead to new compounds. For
example, Wechsler has shown that ozone, either from ofce machines
or entrained from outdoors, may interact with 4-phenyl- cyclohexene
and generate adlehydes. Primary Etiologic Theories Volatile Organic
Compounds Buildings have always relied on general dilution
strategies for pollutant removal, but designers have assumed that
humans were the primary source of pollutants. Emissions from solid
materials (e.g., particle board desks, carpeting, and other
furniture), from wet products (e.g., glues, wall paints, and ofce
machine toners), and personal products (perfumes) have been
recognized as contributors to a complex mixture of very low levels
of individual pollutants as described by Hodgson and co-workers.
Several studies suggest that the presence of reactive VOCs, such as
aldehydes and halogenated hydrocar- bons, is associated with
increasing levels of symp- toms. Ofces with higher complaint rates
showed greater loss of VOCs between incoming and outgoing air than
did ofces with lower complaints. In a prospective study of schools,
short-chain VOCs were associated with symptom development. In an-
other survey, higher personal samples for VOCs using a screening
sampler that overreacts to reactive VOCs such as aldehydes and
halogenated hydrocar- bons were associated with higher symptom
levels. In that study, women had higher levels of VOCs in their
breathing zone, suggesting another potential expla- nation for the
increased rate of complaints among women. VOCs might adsorb onto
sinks, such as eecy surfaces, and be reemitted from secondary
sources. The interaction of ozone and relatively non- irritant VOCs
to form aldehydes is also consistent with this hypothesis. Although
many individual agents are usually present, they are present only
at concentrations well below those needed to cause irritation.
Modeling the irritant effects of such complex mix- tures, such as
that reported by Alarie and co-work- ers, has led to the
development of a quantitative structureactivity relationship for
irritation. Under Table 4 Principal pollutant categories (American
Thoracic Society) Bioaerosols Combustion Environmental tobacco
smoke Radon Volatile organic compounds Fibers Sick Building
Syndrome 11
12. normal conditions, with usual sources and standard
ventilation rates, concentrations should not reach ir- ritant
levels. On the other hand, in the presence of unusual sources
(renovation, unusual ofce condi- tions) or inadequate ventilation,
and especially in the setting of reactive species coexposure,
concentrations are very likely to reach irritating levels.
Bioaerosols Bioaerosols grow in moisture lms on surfaces. Several
studies have suggested that bioaerosols may contribute to occupant
discomfort through several different mechanisms: irritant
emissions; release of fragments, spores, or viable organisms
leading to all- ergy; and secretion of complex toxins. Several
studies suggest a relationship between symptoms indoors and
airborne endotoxin levels. The endotoxin concentra- tions on
cooling coils themselves are better predictors of irritation than
airborne bacteria or endotoxin measurements. This suggests that
some bacterial component, possibly endotoxin, perhaps in combina-
tion with other bioaerosols, plays an important role in generating
symptoms and that moisture and grow- th on the coils rather than in
the air or ductwork plays a role in generating symptoms. Clearly,
heating, ventilating, and air-conditioning systems may be sources
for microorganisms. Fundamentally, the pres- ence of moisture
always raises the suspicion of po- tential cause. Bulk moisture
incursion, through roof defects, wall penetration, below-grade
seepage, or in- ternal leaks, may generate problems. The presence
of moisture barriers in perimeter walls also presents an
opportunity for condensation. Especially in the set- ting of
negative pressure in the building, pulling moisture towards such
barriers (such as vinyl wall paper), bioaerosols may grow and cause
problems. They have also been noted in building construction
materials (as a result of improper curing) and in ofce dust. The
presence of sensitizers in the ofce environment, such as dust mites
or cat danders brought in from home on clothing, presents another
interesting exposure though not likely one of sub- stantial
importance. Psychosocial Aspects of Work In all studies in which it
has been examined, worker stress was clearly associated with SBS
symptoms. Workers reactions to job pressures, such as task conicts,
and outside pressures, such as spousal or parental demands, may
lead to the subjective expe- rience of stronger irritation. At
times, such experi- ences may result at least in part from poor
supervisory practices. In addition, the persistence of irritants
leading to subjective irritation may reinforce work stress.
Conclusion The SBS is a phenomenon experienced by individu- als,
usually seen in groups, associated with engin- eering deciencies,
and likely caused by a combination of pollutants representing a
variety of pollutant categories. As with all disease, a compo- nent
of personal psychology serves as an effect mod- ier contributing to
varying degrees of symptom intensity at any given level of
distress. See also: Behavioral Toxicology; DoseResponse Rela-
tionship; Exposure Assessment; Mixtures, Toxicology and Risk
Assessment; Multiple Chemical Sensitivities; Neuro- toxicity;
Pollution, Air Indoor; Psychological Indices of Toxicity;
Respiratory Tract; Sensory Organs. Further Reading Abraham MH,
Andonian-Haftvan J, Cometto-Muniz JE, and Cain WS (1996) An
analysis of nasal irritation thresholds using a new solvation
equation. Fundamental and Applied Toxicology 31: 7176. Alarie Y,
Schaper M, Nielsen GD, and Abraham MH (1998) Structureactivity
relationships of volatile organic chemicals as sensory irritants.
Archives of Toxicology 72: 125140. Boswell RT, DiBerardinis L, and
Ducatman A (1994) De- scriptive epidemiology of indoor odor
complaints at a large teaching institution. Applied Occupational
and Environmental Hygiene 9: 281286. Cone J and Hodgson MJ (eds.)
(1989) Building-associated illness and problem buildings.
State-of-the-Art Reviews in Occupational Medicine 4: 575802. Doty
RL, Cometto-Muniz JE, Jalowayski AA, et al. (2004) Assessment of
upper respiratory tract and ocular irri- tative effects of volatile
chemicals in humans. Critical Reviews in Toxicology 34: 158.
Hodgson MJ, Levin H, and Wolkoff P (1994) Volatile organic
compounds and the sick-building syndrome. Journal of Allergy and
Clinical Immunology 94: 296 303. Lockey R and Ledford D (eds.)
(1994) Symposium on the sick-building syndrome. Journal of Allergy
and Clinical Immunology Suppl. 2, Pt. 2: 214365. Mendell MJ (1993)
Non-specific symptoms in ofce work- ers: A review and summary of
the literature. Indoor Air 4: 227236. Menzies D, Popa J, Hanley JA,
Rand T, and Milton DK (2003) Effect of ultraviolet germicidal
lights installed in ofce ventilation systems on workers health and
well- being: Double-blind multiple crossover trial. Lancet 362:
17851791. Middaugh DA, Pinney SM, and Linz DH (1992) Sick building
syndrome: Medical evaluation of two work 12 Sick Building
Syndrome
13. forces. Journal of Occupational Medicine 34: 1197 1204.
Molhave L and Nielsen GD (1992) Interpretation and lim- itations of
the concept Total volatile organic com- pounds (TVOC) as an
indicator of human responses to exposures of volatile organic
compounds (VOC) in in- door air. Indoor Air 2: 6577. Selzer J (ed.)
(1995) Illnesses associated with indoor environments.
State-of-the-Art Reviews in Occupational Medicine 10: 1245.
Wechsler CJ (1992) Indoor chemistry: Ozone, volatile organic
compounds, and carpets. Environmental Science and Technology 26:
23712377. Woods JE (1989) Cost avoidance and productivity in own-
ing and operating buildings. Occupational Medicine 4(4): 753770.
World Health Organization (WHO) (1987) Air Quality Guidelines for
Europe. Copenhagen: WHO Regional Ofce for Europe. Silent Spring
Michael A Kamrin & 2005 Elsevier Inc. All rights reserved.
Introduction In the period following World War II, there was a
great increase in industrial production in the devel- oped world.
Not only were existing products manu- factured in larger numbers,
but also a large number of new synthetic chemicals were developed.
These included innovative structural materials, such as plastics,
new and more effective pharmaceuticals and more effective pest
control chemicals. Many of these new compounds rapidly gained
widespread use in the developing as well as the developed world.
This increase in industrial production was soon accompanied by
concerns about the environmental consequences of the efuents from
production facili- ties as well as the new chemicals themselves.
Graphic pictures alerted the public to the problems of decreasing
air quality, and increasing amounts of waste efuents reaching
surface waters. These included images of thick smoke bellowing from
fac- tories and res in rivers, such as the Cuyahoga. The problem
was international in scope as was illustrated by the discovery of
serious human health impacts around Minamata Bay, Japan due to
ingestion of sh contaminated with methylmercury formed from efuents
emitted by an industrial facility on the bay. Complementing this
boom in industrial produc- tion was an great increase in the use of
agricultural chemicals, both fertilizers and pesticides. In
addition to an increase in the amounts applied, the types of
pesticide chemicals used changed to those that were long lasting,
such as the organochlorines. The most prominent example of this
class of pesticides is DDT. There were two main types of concerns
about these persistent pesticides one was their impact on birds and
wildlife and the other their impact on hu- man health. The former
was illustrated by the reports in the late 1950s that DDT usage was
linked to the decimation of the robin population on the Michigan
State University campus. The latter concern was il- lustrated by
the great cranberry scare that occurred right before Thanksgiving
in 1958 when it was thought that pesticide contamination of
cranberries would lead to cancer in people who ate them. It was
also the year that the Congress passed the so-called Delaney
Amendment that forbid the use of any food additive that might be
linked to cancer in laboratory or epidemiological studies. Silent
Spring It is against this background that Silent Spring, writ- ten
by Rachel Carson, was published in 1962. The book was a polemic
that focused on the impacts or potential impacts of pesticides on
both humans and their environment. It was a call for people to be
much more aware of the seriousness of the problems caused by these
synthetic chemicals and to take actions to minimize and/or
eliminate their use. The author recommended that chemical control
of pests be replaced by biological controls and that persistent
chemicals, such as DDT, be taken off the market. The impact of this
book was enormous as it seemed to coalesce the diverse and growing
concerns of the public about damage to the environment and public
health by industry. It contributed strongly to the rise and
expansion of the environmental movement in the mid- to late 1960s
and to the establishment of a number of environmental protection
laws and policies in the United States and elsewhere in the 1970s.
A very important result of this environmental movement was the
creation of the US Environmental Protection Agency. In addition to
catalyzing organizational change, it also led to specific actions
that were called for in Silent Spring, particularly the banning of
DDT use in the United States which occurred in 1972. While the
focus of Silent Spring was pesticides, the environmental movement
that grew out of it was Silent Spring 13
14. much broader and had the goal of limiting the use and
disposal of a wide variety of industrial chemi- cals. Signal
events, such as Love Canal, led to efforts in particular directions
other than limiting pesticide use. In the case of Love Canal, this
direction was the clean-up of hazardous wastes from the past. How-
ever, efforts to force a reduction in pesticide usage also
continued unabated. These efforts have led to increased reliance on
a combination of methods for pest control including both chemical
and biological controls, a technique known as integrated pest
management (IPM). The increasing use of IPM has led to a decreasing
use of pesticides. The continuing public concern about pes- ticides
and other chemicals used in food production has been the impetus
for a growing organic food movement. At least in the United States,
a signicant number of people are willing to pay a premium for foods
that are certied as having been grown without the use of pesticides
or other commercial chemicals. Indirectly, this movement has also
led to the development of agricultural biotechnology, a eld that
focuses on altering crop plants to reduce the need for pesticide
applications. This includes re- search to develop plants that
produce their own nat- ural pesticide as well as crop plants that
are resistant to synthetic pesticides. Plantings of bioengineered
crops have rapidly increased in recent years and a majority of some
crops grown in the United States are products of this technology.
Summary The publication of Silent Spring was a seminal event in the
environmental movement in the United States and, later, abroad.
Prior to the book there was slowly increasing public recognition of
environmental prob- lems due to industrial efuents and use of
certain synthetic chemicals. Afterwards, the environment became an
overriding issue to many Americans and an environmental movement
arose that is still going strong. While there are still questions
about the wis- dom of some of the recommendations that were made in
Silent Spring, there is no question that the book has led to a
different way of looking at our environment and the effects of some
aspects of hu- man progress on this environment. From the
toxicological perspective, it is clear that much of the research
that has been performed in the past four decades has resulted from
concerns that were raised in Silent Spring. These include studies
of the adverse effects on humans and other organisms of pesticides
and other chemicals in our environment as well as basic research on
mechanisms of toxicity. It is evident that this type of research
will continue as questions still remain about well known as well as
newly discovered chemicals in our environment. See also: DDT
(Dichlorodiphenyltrichloroethane); Pesti- cides. Further Reading
Carson R (1962) Silent Spring. New York: Fawcett Crest. Marco GJ,
Hollingworth RM, and Durham W (1987) Silent Spring Revisited.
Washington, DC: American Chemical Society. vanEmden HF and Peakall
DB (1996) Beyond Silent Spring: Integrated Pest Management and
Chemical Safety. London: Chapman and Hall. Silica, Crystalline Kent
E Pinkerton and Randal J Southard & 2005 Elsevier Inc. All
rights reserved. * REPRESENTATIVE CHEMICALS: Quartz; Cristobalite;
Stishovite; Tridymite; Coesite * SYNONYM: Silicon dioxide *
CHEMICAL FORMULA: SiO2 Crystalline silica, also called free silica,
is dened as silicon dioxide (SiO2). This chemical formula
represents a very sta- ble form of silicon, wherein the Si is
completely po- lymerized through SiO bonds in three dimensions *
CHEMICAL STRUCTURE: Crystalline silica represents a form of silica,
which is in a highly organized, framework pattern. The term
crystalline refers to the orientation of SiO2 molecules in a xed
pat- tern as opposed to random molecular arrangem- ent dened as
amorphous, noncrystalline, or short-range order. The oxygen and
silicon atoms of silicon dioxide are arranged in a three-dimen-
sional pattern repeated indefinitely in three direc- tions, forming
the crystalline structure Uses/Occurrence in Nature The most common
hazard for exposure to crystalline silica occurs with sandblasters
who use sand for cleaning of surfaces, thus generating dust clouds
of freshly fractured crystalline silica. Other occupations include
farm labor where mineral dusts are generated 14 Silica,
Crystalline
15. in eld preparation and processing of crops, partic- ularly
in arid to semiarid regions where irrigation is required for crop
production. Although silica is only one constituent of mineral
dust, it can represent up to 15% of the respirable dust present in
agricultural settings because quartz is so abundant in most soils.
The proportion of quartz in respirable dust will thus be related to
soil mineralogy and the relative abun- dances of the sand, silt,
and clay fractions in the soil. Other compounds in which
crystalline silica may be found include gravel, slate, diatomaceous
earth, con- crete, mortar, plaster, refractory materials, pottery
clay, limestone, shale, bricks, and abrasives. The three most
common crystalline forms of silica encountered are cristobalite,
tridymite, and quartz. Quartz is the most common crystalline form
of silica encountered in nature. Quartz is present as al- pha and
beta (high temperature) forms. Alpha quartz is the most common
form, and is found in large quantities in rocks and soils
worldwide. That quartz is among the most abundant minerals in many,
if not most, soils is a reection of its chemical stability and
resistance to weathering. In fact, quartz is so prevalent that the
term quartz is often used in place of crystalline silica. Coesite
and stishtovite are formed at high pressure (e.g., meteorite impact
cra- ters), whereas tridymite and cristobalite form at high
temperature (e.g., volcanic rocks). Other than alpha quartz, all of
these forms are metastable at earth surface temperatures and
pressures and will slowly convert to alpha quartz given enough
time. Micro- crystalline varieties of silica also include small
grains of this material, possibly combined with amorphous silica.
Tripoli, int, chalcedony, agate, onyx, and silica our are examples.
Background Information Silicosis is the oldest known occupational
lung dis- ease. Ancient Greeks were familiar with lung disease in
quarry workers (Hippocrates) and the fact that respirators could
prevent the disease (Pliny). Agricola (1566) described disease in
stone cutters as later did Ramazini (1713). By 1917, the US Public
Health Service identied sand blasters and foundry workers to be at
high risk of silicosis. As the twentieth century progressed,
silicosis was the reference to which newer diseases were compared.
Exposure Routes and Pathways Exposure routes are primarily by
inhalation. The grea- test hazards for exposure to crystalline
silica are typ- ically found in the workplace. When crystalline
silica becomes small enough (i.e., o10 mm in diameter), these
materials can become aerosolized and are able to enter the
respiratory tract where they can deposit along the tracheobronchial
tree or into the deep re- cesses of the lung where gas exchange
takes place (i.e., alveoli). Bulk crystalline silica is dened by
the size of the individual particles. In soils terminology, for ex-
ample, sand is composed of grains 502000 mm in diameter, silt is in
the 250 mm range, while clay-size particles are less than 2 mm in
diameter. Crystalline silica is considered respirable or inhalable
when par- ticles are less than 10 mm in diameter (i.e., in the silt
and clay sizes). Mechanism of Toxicity Although a number of
theories exist to explain the potential mechanism of toxicity to
crystalline silica, the primary cause is described as membrane
damage occurring to cells that ingest these tiny particles. It is
thought that once crystalline silica is ingested into a cell, free
radical oxygen species can be generated from the surface of the
particle leading to lipid peroxidation and membrane damage followed
by release of lysosomal contents and lysis of the cell, resulting
in cell death. This process creates a vicious cycle where
crystalline particles are taken up again into other cells that will
undergo the same sequence of events. Although the precise events to
drive this cell injury process are unclear, it has been observed
that freshly fractured surfaces of crystalline silica more readily
generate free radicals to damage the membrane of cells taking up
these particles, thus producing greater and more rapid cell injury.
This may explain, in part, the hazardous condition creat- ed in
sandblasting where silica particles may be fur- ther fractured in
the cleaning process. The acute toxicity of exposure to crystalline
silica for both animals and humans follows a similar mechanism with
rapid ingestion of particles into cells, primarily alveolar
macrophages, and subsequent damage to lipid membranes and the lytic
death of these cells. This repetitive process results in inammatory
events leading to the inux of numerous macrophages into the
alveolar air spaces. Pulmonary silicosis occurs by way of breathing
these particles over short to long periods of time. The underlying
mechanism for this disease involves the ingestion of silica
particles by macrophages in an at- tempt to remove them from the
lungs. However, sil- ica particles produce membrane damage and
death to these cells. The repetitive process of uptake and re-
lease from macrophages leads to the further release of hydrolytic
enzymes and mediators that stimulate the inux of inammatory cells
and laying down of collagen by broblasts in an abnormal pattern to
Silica, Crystalline 15
16. produce diffuse interstitial lung disease or pulmonary
brosis. Fibrotic changes in the lungs are a reection of a prolonged
injury process to macrophages with the accompanying deposition of
collagen by bro- blasts to bring about scar tissue formation. This
scarring process leads to the loss of alveolar airspace with
excessive amounts of collagen bers forming wherever quartz
particles have been deposited and/or translocated in the lungs. The
pattern of scarring associated with silicosis is typically found to
be more prevalent in the upper lobes of the lung in a nodular
pattern, leading to the complete obliteration of alveolar air
spaces in affected sites. Acute and Short-Term Toxicity (or
Exposure) In both animal and human studies, the toxicity of
crystalline silica is manifested acutely as an inam- matory process
with the inux of a large number of macrophages into the alveolar
airspaces of the lungs. Chronic Toxicity (or Exposure) Chronic
toxicity of crystalline silica in both animals and humans results
in a patchy nodular disease known as pulmonary silicosis. Both
animal and human studies demonstrate the persistence of lung
inammation associated with excess collagen deposi- tion to form
nodular as well as diffuse brotic lesions throughout the lungs. The
disease process of silicosis is incurable and nonreversible. the
disease progress, breathing becomes labored and more difcult, and
can result in death in extreme cases. Symptoms of silicosis include
cough, shortness of breath, wheezing, and repeated chest illnesses.
The diagnosis of a chronic disease due to silicosis is determined
through pulmonary function tests, chest X-rays, and history of
occupational exposure to silica. In addition to the disease process
of silicosis, inha- lation of crystalline silica has been
associated with oth- er diseases such as bronchitis and
tuberculosis. There is also some indication of an association with
lung cancer. In Vitro Toxicity Data Crystalline silica is toxic to
cells in vitro, and it is commonly used as a positive control
material in cytotoxicity testing in cell culture systems. Exposure
Standards and Guidelines The US Occupational Safety and Health
Adminis- tration mineral dust standards for occupational ex- posure
to crystalline silica depend on the actual composition of the
sample. As outlined in the 1974 Center for Disease Con-
trol/National Institute for Occupational Safety and Health
publication, Occupational Exposure to Crys- talline Silica,
employees who are exposed to free sil- ica must be apprised at the
beginning of their employment of the hazards, relevant symptoms,
appropriate emergency procedures, proper condi- tions and
precautions for safe use or exposure. The following warning is
required to be posted in both English and the predominant language
of non- English-speaking workers potentially exposed to free silica
dust: WARNING! CONTAINS FREE SILICA DO NOT BREATHE DUST May Cause
Delayed Lung Injury (Silicosis) Further Reading Criteria for a
Recommended Standard for Occupational Exposure to Crystalline
Silica, HEW Publication No. (NIOSH) 75-120. Washington, DC: Center
for Disease Control, National Institute for Occupational Safety and
Health, 1974. Drees LR, Wilding LP, Smeck NE, and Senkayi AL (1989)
Silica in soils: Quartz and disordered silica polymorphs. In: Dixon
JB and Weed SB (eds.) Minerals in Soil Environments, 2nd edn.
Madison, WI: Soil Science Society of America. Goldsmith DF, Winn
DM, and Shy CM (eds.) (1996) Silica, Silicosis, and Cancer:
Controversy in Occupational Med- icine. New York: Praeger. Relevant
Websites http://geology.usgs.gov Crystalline Silica Primer, Branch
of Industrial Minerals, US Department of the Interior, Washington,
DC, 1978. http://www.osha.gov The US Occupational Safety and Health
Administration mineral dust standards for occu- pational exposure
to crystalline silica depend on the ac- tual composition of the
sample. Interested readers may consult Table Z-3 in the website. 16
Silica, Crystalline
17. Silver Shayne C Gad & 2005 Elsevier Inc. All rights
reserved. This article is a revision of the previous print edition
article by Arthur Furst and Shirley B Radding, volume 3, p. 144,
& 1998, Elsevier Inc. * REPRESENTATIVE CHEMICALS: Silver
chloride (AgCl); Silver nitrate (AgNO3); Silver cyanide (AgCN) *
CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 7440-22-4 *
SYNONYM: Plata * CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Precious
metals * CHEMICAL FORMULA: Ag Uses Silver is used extensively in
jewelry, eating utensils, coins, batteries, and dental amalgams.
Silver solu- tions are used as antiseptics, astringents, and ger-
micides. In some domestic water puriers, silver is used to remove
chlorine and kill bacteria. It has also been used in hair dyes.
Medicinal use includes silver nitrate eye drops for newborns (a
legal requirement in some states) and use as an antimicrobial on
some implantable medical devices. The main industrial use of silver
is in the form of silver halide for the pho- tographic industry.
Silver halide is photosensitive, making it an ideal coating for
photographic plates. Background Information Silver is one of the
earliest known metals. Silver has no known physiologic of biologic
function, though colloidal silver is widely sold in health food
stores. Exposure Routes and Pathways Ingestion and inhalation are
possible routes of ex- posure; dermal absorption of silver is
unlikely. Silver is not a normal constituent of foodstuff. Very
little, if any, silver is detected in domestic drinking water;
however, some domestic water-purifying systems contain silver.
Toxicokinetics Approximately 10% of ingested silver is absorbed.
Inhaled silver can be absorbed from the lungs. Silver can be
absorbed across oral mucosa. Once absorbed, silver tends to
precipitate in various tissues, as the afnity for sulde by silver
is immense. Silver tends to complex with sulfhydryl groups on
macromole- cules. It is carried by globulins in the serum and forms
complexes with the serum proteins, mainly albumin, which accumulate
in the liver. Silver is ex- creted in the feces (primarily) and
urine. Mechanism of Toxicity While specific mechanisms of toxicity
are unclear, high afnity for sulfhydryl groups on proteins could
lead to alteration of a number of cellular processes. Acute and
Short-Term Toxicity (or Exposure) Animal The acute toxicity of
metallic silver and water-solu- ble compounds is moderate. The oral
LD50 in mice for colloidal silver was 100 mg kg 1 and relatively
similar for the water-soluble compounds silver ni- trate (50129 mg
kg 1 ) and silver cyanide (LD50 in rats, 125 mg kg 1 ). Silver
nitrate appears much less toxic in rabbits by the oral route (800
mg kg 1 ). The insoluble silver oxide was reported to exhibit an
LDLo of 42 g kg 1 in rats. Human Acute oral exposure to silver
nitrate has led to irri- tation and corrosion in the
gastrointestinal tract, abdominal pain, diarrhea, vomiting, shock,
convuls- ions, and death in humans. Silver or silver nitrate can
lead to respiratory irritation with inhalation expo- sures. Silver
nitrate is highly irritating to the skin, mucous membranes, and
eyes. Insoluble silver com- pounds (e.g., silver chloride, silver
iodide, and silver oxide) are relatively benign. Chronic Toxicity
(or Exposure) Animal With selenium or Vitamin E decient diets,
repeated exposure to silver (76 ppm in the drinking water for 52
days) in rats elicited hepatic necrosis and ultra- structural
changes in the liver indicative of oxidative damage. This toxicity
may be related to a silver- induced selenium deciency and
impairment of synthesis of the enzyme glutathione peroxidase.
Dietary supplementation with selenium or Vitamin E prevented such
changes. Mice exposed to silver nitrate in the drinking water for 4
months exhibited Silver 17
18. silver-containing deposits in the central nervous sys- tem
and reduced motor activity. Human Workers chronically exposed to
silver have experi- enced industrial argyria, an occupational
disease characterized by discoloring of the skin. Blue gray patches
are noted on the skin and possibly the conjunctiva of the eye or
the mucous membranes. Long-term exposure can result in extensive
skin dis- coloration, mainly on the parts of the body that are
exposed to light (e.g., the face). Light may decom- pose the silver
complex, resulting in extremely ne silver that gives the skin a
metallic sheen. In some cases, the dark patches turn black. Chronic
bronchi- tis has been reported following medicinal use of col-
loidal silver. Potential symptoms of overexposure are bluegray
eyes, nasal septum, throat, and skin. The discoloration can be
permanent. Clinical Management Clinical management is supportive
and there no known active treatment. Administration of table salt
will help precipitate soluble silver as the insoluble silver
chloride. British antilewisite (2,3-dimercapto- propanol) has not
proven useful. Environmental Fate Silver exists in four oxidation
states (0, 1 , 2 , and 3 ). Silver occurs primarily as sulfides
with iron, lead, tellurides, and with gold. Silver is found in sur-
face waters as sulde, bicarbonate, or sulfate salts, as part of
complex ions with chlorides and sulfates and adsorbed onto
particulate matter. Silver is released through natural processes,
for example, erosion of soils. Sources of atmospheric contamination
arise from processing of ores, steel refining, cement man-
ufacture, fossil fuel combustion, and municipal waste incineration.
Of anthropomorphic release, over 75% was estimated to be from
disposal of solid waste. Ore smelting and fossil fuel combustion
can emit ne particulates that may be transported long distanc- es
and deposited with precipitation. The major source of release to
surface waters is efuent from photogra- phic processing. Releases
from the photographic industry and from disposal of sewage sludge
and refuse are the major sources of soil contamination with silver.
Silver can leach into groundwater; acidic conditions increases
leaching. Silver can be biocon- centrated in sh and invertebrates.
Ecotoxicology The no-observed-effect concentration of silver
nitrate in a 28 day toxicity test using a marine invertebrate
(Americamysis bahia) was 34 mg l 1 . The 96 h LC50 value was 260 mg
l 1 . In a 21 day toxicity study using the freshwater invertebrate
Daphnia magna, 5 mg Ag l 1 (as silver nitrate) under static
conditions, 20% mortality was noted (0% in controls). Silver caused
a signicant reduction of reproductive per- formance (14% decrease
in the number of neonates). Silver caused a 65% decrease in whole
body sodium concentration and a 60% increase in whole body Na ,K
-ATPase activity. Silver nitrate (10 mg l 1 ) elicited a 35%
reduction in whole body sodium and increases in daily mor- tality
in developing rainbow trout. Exposure to 0.1 mg l 1 silver led to
reduction in growth. Exposure Standards and Guidelines The American
Conference of Governmental Indus- trial Hygienists threshold limit
value (TLV) time- weighted average is 0.1 mg m 3 for silver metal;
the TLV is 0.01 mg m 3 for soluble silver compounds. See also:
Metals. Further Reading Dart RC (2004) Medical Toxicology, 3rd
edn., pp. 1459 1461. Baltimore: Williams & Wilkins. Relevant
Websites http://www.atsdr.cdc.gov Agency for Toxic Substances and
Disease Registry. Toxicological Prole for Silver.
http://cira.ornl.gov Toxicity Summary for Silver (from the Oak
Ridge National Laboratory). 18 Silver
19. Sister Chromatid Exchanges David A Eastmond & 2005
Elsevier Inc. All rights reserved. This article is a revision of
the previous print edition article by Ann D Mitchell, volume 3, pp.
144146, & 1998, Elsevier Inc. Sister chromatid exchanges (SCEs)
are reciprocal exchanges of segments of chromatids: chromatids are
the subunits of chromosomes, as visualized in meta- phase, which
become daughter chromosomes upon completion of cell division.
Sister chromatid ex- changes were discovered by J.H. Taylor in the
late 1950s in experiments using the pulsed uptake of 3 H-labeled
thymidine (TdR) in growing Vicia faba root tips, followed by
autoradiography, to dene the pattern of DNA replication in
chromosomes. Before Taylors experiments, it was thought that one
chromatid might be composed of newly synthe- sized DNA and the
other of preexisting DNA. However, Taylor found that the DNA
replicated semiconservatively, that is, in the rst metaphase after
[3 H]TdR incorporation (M1) each chromatid was 3 H-labeled, which
demonstrated that the chro- matid was duplex, containing both
preexisting and newly synthesized DNA. Furthermore, in the second
division after 3 H incorporation (M2) one chromatid was labeled and
the other was unlabeled, that is, both the preexisting and the
newly synthesized DNA in each daughter chromosome had served as a
tem- plate for the next round of DNA replication, again resulting
in two sister chromatids. Taylor also noted that occasionally in M2
one otherwise labeled chro- matid had an unlabeled segment and,
when this occurred, the corresponding segment of the other- wise
unlabeled chromatid was labeled with [3 H]TdR, indicating a
reciprocal exchange of segments be- tween the two sister
chromatids, that is, a sister chromatid exchange. The development
of SCE assays for genetic toxic- ology research and testing did not
occur until the early 1970s, a time when a plethora of approaches
were identied for assessing the potential genetic hazards of
chemical exposure. Rather than using [3 H]TdR and autoradiography
to visualize SCEs, the dened approaches are usually based on the
more precise and efcient incorporation of bromode- oxyuridine
(BrdU), an analog of thymidine, in two rounds of replication
followed by Giemsa, or uo- rescence-plus-Giemsa, staining of the
chromosomes. Because of semiconservative DNA replication, the
chromatids are equally stained in M1 chromosomes, and the M2
chromosomes possess one chromatid that is half-BrdU-substituted and
one fully substituted chromatid that is stained more lightly than
the other. SCEs are revealed in M2 chromosomes by an alter- nating
or harlequin pattern of darkly and lightly staining chromatid
segments. This approach has also been used to reveal chemi- cal-
and concentration-related delays in the progre- ssion of cells
through the cell cycle as a preliminary test for selecting exposure
conditions for chromo- somal aberration assays. The objective of
such pre- liminary tests is to dene exposure conditions and harvest
times that will yield sufcient numbers of rst division, M1, cells
for cytogenetic analysis. This is benecial because a high
percentage of chromo- somally damaged cells are often unable to
progress to the second and following metaphases. In vitro SCE
assays are routinely conducted in cultured Chinese hamster ovary
(CHO) cells or human lymphocytes, and assessments of SCEs in human
lymphocytes have been used for human popu- lation monitoring.
Following in vivo exposure, SCEs are usually visualized in bone
marrow cells from mice implanted with BrdU-containing tablets (or
pumps). Such SCE assays have been used to test several hundred
chemicals and have been shown to be highly sensitive and, in
comparison to conventio- nal assays for chromosomal aberrations, to
be more rapid, less subjective, and capable of detecting effects at
lower dose levels. SCE assays would, therefore, appear to be uni-
quely suited for inclusion in initial batteries of tests to assess
genotoxicity. However, while this was initially perceived to be the
case, the use of SCE as- says for genotoxicity testing has been
greatly reduced for several reasons. First, it was found that the
use of BrdU (or [3 H]TdR) can induce SCEs; thus, there was concern
that when SCE frequencies were elevated following chemical
exposure, synergistic effects were being measured, which might not
be as appropriate for risk assessment as the measurement of direct
effects. Second, although there is strong evidence that SCEs result
from misreplication of a damaged DNA template, probably from
recombination at a stalled replication fork, there was uncertainty
concerning whether to classify SCE assays as cytogenetic tests, as
a measure of the repair of DNA damage, or as an independent
category of test. Third, alarm was ex- pressed when common
chemicals such as NaCl (i.e., table salt) were found to be positive
in in vitro SCE assays. It was subsequently shown that in in vitro
assays, particularly in the presence of exogenous metabolic
activation, such false-positive results could be eliminated if
exposure conditions are monitored Sister Chromatid Exchanges
19
20. and adjusted to preclude acidic pH shifts and high
osmolality. However, the most signicant reason for an absence of
regulatory requirements for the routine use of SCE tests and their
discontinuation by indus- try was the outcome of a National
Toxicology Program (NTP) comparison of the concordance of results
from four in vitro tests with results from ro- dent carcinogenicity
bioassays. Specifically, the NTP studies conducted by Tennant and
colleagues found that, although few positive results were obtained
for noncarcinogens in the Salmonella typhimurium reverse mutation
assay (Ames test) or in the test for chromosomal aberrations in CHO
cells, an unac- ceptably high number of false-positive results were
obtained in the in vitro SCE assay. Thus, SCE tests have been
largely discontinued by industry and are recommended by regulatory
agen- cies on a limited basis. However, this assay continues to be
used as a research tool and in some regulatory settings. For
example, despite its poor concordance, the SCE assay continues to
be used by the NTP, in part because SCE techniques are sufciently
similar to those used for in vitro chromosomal aberration assays so
that the two tests can efciently be used in parallel by cytogenetic
testing laboratories. Similarly the measurement of SCEs for
population monitoring has also diminished in recent years as a
result of several prospective studies whose objective was to
determine if cytogenetic assays had predictive value for future
cancer risk. In these studies, no cor- relation was seen between
SCE levels and future cancer risk whereas good correlations were
seen between the frequency of chromosomal aberrations and the
subsequent development of cancer in the study groups. Recent
evidence indicates that SCEs are primarily formed as the result of
homologous recombination so that SCE frequencies represent a
measure, not only of mutagen exposure but also of the efciency of
DNA repair. As a result, a direct correlation between SCEs and
cancer incidence may not be expected. In spite of the recent
developments, there continues to be uncertainty about the
underlying mechanisms by which SCEs are formed, and how DNA damage
or disturbances in DNA synthesis stimulate SCE for- mation. Based
on our current understanding, SCEs are probably best regarded as a
general indicator of mutagen exposure rather than as a specific
measure of mutagenic effects. See also: Ames Test; Analytical
Toxicology; Aneuploidy; CarcinogenDNA Adduct Formation and DNA
Repair; Chromosome Aberrations; Developmental Toxicology; Dominant
Lethal Tests; Host-Mediated Assay; Molecular Toxicology Recombinant
DNA Technology; Mouse Lymphoma Assay; Toxicity Testing,
Mutagenicity. Further Reading Hagmar L, Bonassi S, Stromberg U, et
al. (1998) Chro- mosomal aberrations in lymphocytes predict human
can- cer: A report from the European Study Group on Cytogenetic
Biomarkers and Health (ESCH). Cancer Research 58: 41174121. Latt
SA, Allen J, Bloom SE, et al. (1981) Sister-chromatid exchanges: A
report of the GENE-TOX program. Muta- tion Research 87: 1762.
Natarajan AT (2002) Chromosome aberrations: Past, present and
future. Mutation Research 504: 316. Perry PE (1980) Chemical
mutagens and sister-chromatid exchange. In: de Serres FJ and
Hollaender A (eds.) Chemical Mutagens: Principles and Methods for
their Detection, vol. 6, pp. 139. New York: Plenum. Sonda E, Sasaki
M, Morrison C, et al. (1999) Sister chro- matid exchanges are
mediated by homologous recombi- nation in vertebrate cells.
Molecular Cell Biology 19: 51665169. Tucker JD, Auletta A, Cimino
MC, et al. (1993) Sister- chromatid exchange: Second report of the
Gene-Tox program. Mutation Research 297: 101180. Skeletal System M
Joseph Fedoruk and Tee L Guidotti & 2005 Elsevier Inc. All
rights reserved. This article describes the structure and function
of the musculoskeletal system and provides an over- view of the
categories of toxic effects that can affect this body system. The
article is divided into two principle parts, which form the main
components of the musculoskeletal system: bone and skeletal muscle.
Bone Bone, a form of connective tissue, composes the skele- tal
system. The skeletal system provides mechanical support for the
body and protects internal organs such as the brain and heart,
which are contained in 20 Skeletal System
21. skull and the chest wall cavity, respectively. The hu- man
skeleton is composed of 206 bones that vary in size and shape and
include at, trabecular, and cuboid bones. The body size and shape
are determined by the skeletal system. Bone serves other functions.
It is a dynamic tissue that plays a vital role in mineral
homeostasis and is a reservoir for several essential minerals
including cal- cium, phosphorus, magnesium, and sodium. Bone houses
the delicate bone marrow that forms blood from hematopoietic cells.
Bone is an extremely vas- cular tissue and receives up to 10% of
the cardiac output. Joints form the sites where bones come together
or articulate. Joints are classied by the type of tissue that lies
between the bones. Joints with brous tissue between the
articulating surfaces are called brous joints and include the
sutures of the skull. Cart- ilaginous joints are united by hyaline
cartilage and are classied into primary and secondary cartilagin-
ous joints. Primary cartilaginous joints do not allow any movement.
Bone is composed of live cells interspersed in an organic matrix.
Inorganic elements or minerals (65%) are deposited into this
organic matrix (35%), which makes bone one of the few tissues that
normally mineralize. The principal inorganic element in bone is
calcium hydroxyapatite (Ca10 (PO4)OH2), which accounts for B99% of
the cal- cium and 80% of the stores of these respective mine- rals
in the body. Calcium hydroxyapatite provides bone with strength and
hardness. The organic matrix provides a degree of elasticity to
bone. The cellular elements of bone include osteo- progenitor
cells, which are pluripotential cells derived from mesenchymal
tissue. Osteoprogenitor cells produce offspring cells that can
differentiate into osteoblasts. Osteoblasts are responsible for the
formation of the organic matrix of the bone into which the mineral
elements can be deposited. Groups of several hundred osteoblastic
cells coordinate activities to facilitate the formation of the
organic matrix. The organic matrix is principally composed of type
I collagen (90%) and several other non- collagenous proteins,
including (1) osteocalci